Tumor-associated monoclonal antibodies (mAbs) are therapeutic agents when utilized as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are particle emitting radionuclides and their relative efficacy is evaluated in appropriate murine tumor xenograft model systems. The radionuclides chosen for study span the range of radionuclidic properties available thereby permitting the assay of the effects of emission energy, half-life, and type of emission. Current research continues to be focused on performing extensive pre-clinical studies with alpha-particle emitting radionuclides 212Pb, 213Bi, and 211At. Ongoing collaborative clinical trials employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or tiuxetan) for sequestering 90Y, however, nearly all of the collaborative clinical trials now employ the third-generation bifunctional chelating agent, CHX-A'' DTPA, for 111In, 90Y, 213Bi, and now potentially 177Lu. Studies initiated this year continue to validate the use of the CHX-A'' DTPA for use in positron emission tomography (PET) imaging with 86Y while that same established chelation chemistry for 213Bi continues to be employed in both pre-clinical and clinical studies. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues primarily in regards to refinements in conjugation chemistry options and radiolabeling improvements. These refinements stem from a combination of expansion to provide agents for peptide chemistry as well as for site-specific conjugation strategies that would be amenable for use with both radio-lanthanides and alpha-particle emitting radionuclides such as 213Bi. In parallel with these refinements, a novel bifunctional cross-bridged cyclam with an active ester moiety was developed for use with Cu-64 that should prove useful for both PET imaging and therapy. Additionally, novel linking chemistry for extant bifunctional chelating agents has been developed that is also amenable to peptide usage and even in use within peptide synthesizer instrumentation. Thus, many of the established agents of the Chemistry Section are now being extended to peptides and other small delivery vectors targeting receptors of interest such as affibodies. Studies with 211At that have been temporarily on hiatus after validation of the most stable 211At linker reagent, N-Me-SAPS, will be resumed later this calendar year to open a parallel investigation to those ongoing with other alpha emitters to treat disseminated intraperitoneal disease. The highly extensive and focused pre-clinical investigation into the use of both 212Bi and 212Pb continues for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian cancer or pancreatic cancer continues to move forward towards a potential clinical trial, however the planned trial using 212Pb has been relocated to UAB due to unresponsive collaborators at the NCI. A pre-IND meeting with the FDA has defined the relevant issues regarding toxicity studies that are required while GMP manufacturing has been initiated by an industrial partner. In addition to evaluation of the efficacy of these radionuclides individually with specific mAbs, the use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues to be systematically investigated. This investigation rests on the hypothesis that single doses of a single, targeted radionuclide lack a rational basis for cancer therapy and that combined modality therapies will achieve significant therapeutic enhancements. Results have indicated that substantial increases in median life expectancy in murine models are possible with single doses of 213Bi or 212Pb conjugated to clinically relevant antibodies such as CC49(Delta)CH2, Herceptin, and now Erbitux. Use of 212Pb in combination with Gemcitabine showed impressive enhanced therapeutic efficacy; fractionated dosing of both 212Pb and Gemcitabine provided evidence that optimization of both drug combination and scheduling will result in extended survival. Studies combining administration of 213Bi or 212Pb with taxol demonstrated significant extension of survival with a very strong dependence on administration scheduling and were recently the topic of a publication in Clinical Cancer Research. A similar line of investigation assessing the impact of combination with carboplatin or cisplatin has also been performed. Fractionation studies of 213Bi with taxol were repeated this year. Preliminary studies with 212Pb-labeled Erbitux (cetuximab) were executed to support another Phase zero 111In imaging trial while also laying the groundwork for delivery of therapeutic radiation targeted to multiple cell surface receptors to address tumor heterogenicity when used in combination with radiolabeled Herceptin. A second anti-EGFR antibody, panitumumab, was similarly studied in the lab since this antibody is not cross-reactive with cetuximab thereby permitting use of all 3 antibodies in combination therapy trials. Results on almost all studies have so far indicated a significant superiority in response for 212Pb over 213Bi that may be solely related to half-life. Studies have been initiated in collaboration with the Gius lab (Radiation Oncology Branch, CCR) to investigate and define the biological mechanisms at the cellular level of both damage response and repair as well as genetic regulation of the cell biology in response to traversal of high-LET radiation both alone and in combination with treatment with chemotherapeutics Collaborative studies continue to be executed with either reagents and/or expertise being supplied to facilitate the ability of extramural researchers to expeditiously perform those experiments required to fully define the actual clinical impact of targeted radiation therapy. To this end, the Section continues to enjoy very strong and potent collaborative relationships with the Metabolism Branch, CCR and with the Ludwig Institute, (Andrew Scott) and has extended this activity to embrace a close collaborative relationship with UAB to translate 212Pb into the first clinical trial of this radionuclide for the treatment of disseminated ovarian cancer.